minocycline and Cerebral-Infarction

Cerebrovascular disease is a major cause of mortality and disability in adults. Diabetes mellitus increases the risk of cerebral ischaemia and is associated with worse clinical outcome following an event. Upregulation of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) in diabetes appears to play a role in vascular complications of diabetes. We hypothesised that inhibition of MMP-2 and MMP-9 by minocycline can be potentiated by aspirin through inhibition of cyclooxygenase-2 and tissue plasminogen activator, resulting in amelioration of clinical cerebral ischaemia in diabetes. In the present study, cerebral ischaemia/reperfusion injury was induced in streptozotocin diabetic rats by 1 h middle cerebral artery occlusion and 24 h reperfusion. Infarct volume, cerebral oedema, neurological severity score and blood-brain barrier disruption were significantly increased in diabetic animals compared with the normoglycemic control group. The combination of aspirin and minocycline treatment significantly improved these parameters in diabetic animals. Moreover, this therapy was associated with significantly lower mortality and reduction in MMP-2 and MMP-9 levels. Our data indicate that combination of aspirin and minocycline therapy protects from the consequences of cerebral ischaemia in animal models of diabetes and is associated with inhibition of MMP-2 and MMP-9. Therefore, this combination therapy may represent a novel strategy to reduce the neurological complications of cerebral ischaemia in diabetes.

Topics: Animals; Aspirin; Blood Glucose; Blood-Brain Barrier; Body Weight; Brain; Brain Edema; Capillary Permeability; Cerebral Infarction; Cyclooxygenase 2 Inhibitors; Cytoprotection; Diabetes Complications; Diabetes Mellitus, Experimental; Drug Synergism; Drug Therapy, Combination; Ischemic Attack, Transient; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Minocycline; Protease Inhibitors; Rats; Rats, Wistar; Severity of Illness Index; Time Factors; Tissue Plasminogen Activator

Thrombolysis with tPA is the only FDA-approved therapy for acute ischemic stroke. But its widespread application remains limited by narrow treatment time windows and the related risks of cerebral hemorrhage. In this study, we ask whether minocycline can prevent tPA-associated cerebral hemorrhage and extend the reperfusion window in an experimental stroke model in rats.. Spontaneously hypertensive rats were subjected to embolic focal ischemia using homologous clots and treated with: saline at 1 hour; early tPA at 1 hour, delayed tPA at 6 hours; minocycline at 4 hours; combined minocycline at 4 hours plus tPA at 6 hours. Infarct volumes and hemorrhagic transformation were quantified at 24 hours. Gelatin zymography was used to measure blood levels of circulating matrix metalloproteinase-9 (MMP-9).. Early 1-hour thrombolysis restored perfusion and reduced infarction. Late 6-hour tPA did not decrease infarction but instead worsened hemorrhagic conversion. Combining minocycline with delayed 6-hour tPA decreased plasma MMP-9 levels, reduced infarction, and ameliorated brain hemorrhage. Blood levels of MMP-9 were also significantly correlated with volumes of infarction and hemorrhage.. Combination therapy with minocycline may extend tPA treatment time windows in ischemic stroke.

Topics: Animals; Biomarkers; Blood-Brain Barrier; Brain Ischemia; Cerebral Hemorrhage; Cerebral Infarction; Drug Administration Schedule; Drug Evaluation, Preclinical; Fibrinolytic Agents; Intracranial Embolism; Male; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Minocycline; Neuroprotective Agents; Rats; Rats, Inbred SHR; Recombinant Proteins; Reperfusion; Thrombolytic Therapy; Time Factors; Tissue Plasminogen Activator

Evidence suggests that activated microglia are detrimental to the survival of new hippocampal neurons, whereas blocking inflammation has been shown to restore hippocampal neurogenesis after cranial irradiation and seizure. The aim of this current study is to determine the effect of minocycline on neurogenesis and functional recovery after cerebral focal ischemia.. Four days after temporary middle cerebral artery occlusion, minocycline was administered intraperitoneally for 4 weeks. BrdU was given on days 4 to 7 after middle cerebral artery occlusion to track cell proliferation. The number of remaining new neurons and activated microglia were quantified in the dentate gyrus. Infarct volume was measured to assess the treatment effect of minocycline. Motor and cognitive functions were evaluated 6 weeks after middle cerebral artery occlusion.. Minocycline delivered 4 days after middle cerebral artery occlusion for 4 weeks did not result in reduction in infarct size but significantly decreased the number of activated microglia in the dentate gyrus. Minocycline also significantly increased the number of newborn neurons that coexpressing BrdU and NeuN without significantly affecting progenitor cell proliferation in the dentate gyrus. Lastly, minocycline significantly improved motor coordination on the rotor rod, reduced the preferential use of the unaffected limb during exploration, reduced the frequency of footfalls in the affected limb when traversing on a horizontal ladder, and improved spatial learning and memory in the water maze test.. Minocycline reduces functional impairment caused by cerebral focal ischemia. The improved function is associated with enhanced neurogenesis and reduced microglia activation in the dentate gyrus and possibly improved neural environment after chronic treatment with minocycline.

Topics: Animals; Anti-Bacterial Agents; Brain Ischemia; Cell Differentiation; Cell Proliferation; Cerebral Infarction; Disease Models, Animal; Drug Administration Schedule; Infarction, Middle Cerebral Artery; Male; Memory; Minocycline; Motor Activity; Nerve Degeneration; Nerve Regeneration; Neurons; Neuroprotective Agents; Nootropic Agents; Rats; Rats, Sprague-Dawley; Stem Cells

Intracerebral hemorrhage (ICH) is a devastating condition currently lacking a defined line of treatment. The inflammatory response that ensues following its onset is thought to contribute to secondary injury following ICH, making inflammation a potential therapeutic target. Minocycline (MC), a commonly used antibiotic that also has anti-inflammatory and anti-apoptotic properties, provides histological protection in several animal stroke models when given soon after injury. However, its ability to provide protection with more clinically relevant delays is unknown. The objective of this study was to examine the effects of MC on histopathological changes and long-term functional outcomes in a collagenase-induced ICH model in rats when drug administration was delayed 3 h following the onset of ICH. In accordance with other studies, MC suppressed microglial/macrophage activation in the peri-infarct region at 5 days based on B4 isolectin histochemistry. However, no reduction in infarct volume was detected at 5 or 28 days post-ICH. Minocycline given for either 5 or 14 days also provided no functional benefit as assessed with a battery of sensory-motor tests (i.e., staircase, cylinder, ladder tests). These findings raise questions about the ability of MC to provide protection in ICH when delay to treatment is increased.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Behavior, Animal; Cerebral Hemorrhage; Cerebral Hemorrhage, Traumatic; Cerebral Infarction; Macrophages; Male; Microglia; Minocycline; Neostriatum; Rats; Rats, Long-Evans; Survival Analysis; Time Factors

Blood-brain barrier (BBB) disruption after stroke can worsen ischemic injury by increasing edema and causing hemorrhage. We determined the effect of microglia on the BBB and its primary constituents, endothelial cells (ECs) and astrocytes, after ischemia using in vivo and in vitro models.. Primary astrocytes, ECs, or cocultures were prepared with or without added microglia. Primary ECs were more resistant to oxygen-glucose deprivation/reperfusion than astrocytes. ECs plus astrocytes showed intermediate vulnerability. Microglia added to cocultures nearly doubled cell death. This increase was prevented by minocycline and apocynin. In vivo, minocycline reduced infarct volume and neurological deficits and markedly reduced BBB disruption and hemorrhage in mice after experimental stroke.. Inhibition of microglial activation may protect the brain after ischemic stroke by improving BBB viability and integrity. Microglial inhibitors may prove to be an important treatment adjunct to fibrinolysis.

Topics: Acetophenones; Animals; Antioxidants; Astrocytes; Blood-Brain Barrier; Brain; Brain Ischemia; Cell Death; Cells, Cultured; Cerebral Hemorrhage; Cerebral Infarction; Coculture Techniques; Endothelial Cells; Glucose; Hydrogen Peroxide; Hypoxia; Male; Mice; Mice, Inbred C57BL; Microglia; Minocycline; Nervous System Diseases; Superoxides; Tumor Necrosis Factor-alpha

Minocycline, a second-generation tetracycline, has been shown to possess neuroprotective effects in animal models of stroke. Pial vessel disruption in adult Wistar rats leads to a cone-shaped cortical lesion and turns into a fluid-filled cavity surrounded by a GFAP+ glia limitans 21 days after injury. This mimics the clinical situation in lacunar infarcts. Minocycline was given intraperitoneally at a dose of 45 mg/kg 1 and 12 h after lesioning, followed by 22.5 mg/kg twice daily until 6 days after lesioning. Control rats received intraperitoneal injections of equivalent volumes of saline. Cavitation was prevented in five out of six minocycline-treated animals and the glia limitans did not appear as the space was filled with GFAP+ reactive astrocytes. However, the number of activated microglia showed no difference between minocycline-treated and -untreated groups. Minocycline did not reduce the number of infiltrating leukocytes, predominately polymorphonuclear neutrophils (PMNs) determined by myeloperoxidase immunoreactivity, or infiltration of CD3+ lymphocytes. The pial vessel occlusion induced a significant upregulation of IL-1beta expression; however, minocycline treatment did not significantly alter this upregulation of IL-1beta. In this study, we found minocycline facilitated the repopulation of the lesion by reactive astrocytes and therefore prevented cavitation; however, we could not identify the molecular signal.

Topics: Animals; Anti-Bacterial Agents; Astrocytes; Brain Ischemia; Cerebral Arteries; Cerebral Cortex; Cerebral Infarction; Chemotaxis, Leukocyte; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Glial Fibrillary Acidic Protein; Gliosis; Interleukin-1; Leukocytes; Male; Microglia; Minocycline; Nerve Degeneration; Neuroprotective Agents; Rats; Rats, Wistar; Treatment Outcome; Up-Regulation